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Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.
- Source :
- Nature Chemical Biology; Jul2015, Vol. 11 Issue 7, p518-524, 7p, 6 Graphs
- Publication Year :
- 2015
-
Abstract
- Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Although a capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2- to 4.5-Å resolution, capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions-important details required for mechanistic understanding. We obtained the missing atomic-level details by iterative computation and confirmed them by systematic site-specific functional tests. We observed that the bound capsaicin takes a 'tail-up, head-down' configuration. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes TRPV1's open state by 'pull-and-contact' interactions between the vanillyl group and the S4-S5 linker. Our study provides a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrates an effective approach to obtain atomic-level information from cryo-EM structures. [ABSTRACT FROM AUTHOR]
- Subjects :
- CAPSAICIN
CHEMICAL structure
ION channels
SPICES
CHEMICAL biology
Subjects
Details
- Language :
- English
- ISSN :
- 15524450
- Volume :
- 11
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Nature Chemical Biology
- Publication Type :
- Academic Journal
- Accession number :
- 103278531
- Full Text :
- https://doi.org/10.1038/nchembio.1835